Project Summary: Pancreatic adenocarcinomas are among the most fatal cancers because of their extensive metastasis to distant organs, even at an early stage of tumor progression. A significant majority of pancreatic cancer patients also suffer from a very poor quality of life due to cachexia. Cachexia not only impedes the response to chemotherapy but also is a major cause of morbidity and mortality. Thus, a basic understanding of the mechanisms that promote cachexia will provide a basis for developing new methods for treatment and will significantly improve the overall quality of life. Tumor cells display alterations in metabolite flux into biosynthetic reactions that induce systemic metabolic effects causing myodegeneration and adipocyte fat depletion. Although some studies have attempted to understand the mechanistic basis of muscle and fat degradation, the metabolic link between the energy need of tumor cells and cachexia syndrome remains largely unexplored. Our preliminary studies identify a number of key metabolic pathways that have increased flux in tumor tissues and muscle specimens from pancreatic cancer patients with cachexia, in comparison to the ones without cachexia. Furthermore, our results suggest that secreted small-molecule metabolites possess cachectic activity independent of the known cachectic agents. Hence, we hypothesize that metabolic flux in tumors and secreted metabolites lead to metabolic alterations in muscle tissues, causing oxidative damage and cachexia. Furthermore, we hypothesize that targeting the metabolic pathways in tumor cells and muscles will diminish cachexia in pancreatic cancer. To test these hypotheses, we propose to elucidate the direct role of metabolites/metabolic pathways in regulating cachexia (Aim 1), to test if catabolic pathways in muscles can be targeted to abrogate cachexia in animal models (Aim 2), and to determine if elevated levels of metabolites in muscle tissues correlate with cachexia onset and prognosis in pancreatic cancer patients (Aim 3). We will validate the increased levels of identified tumor cell-secreted metabolites in the plasma specimens from cachectic cancer patients in comparison to that of the non-cachectic cancer patients and characterize the mechanistic aspects of direct myodegeneration caused by such metabolites in animal models. We will also determine if their levels correlate with the extent of myodegeneration in patients. Furthermore, we propose to evaluate the therapeutic efficacy of targeting the underlying metabolic pathways for diminishing cachexia. Overall, these studies will utilize highly innovative concepts and approaches to address the role of metabolites and metabolic pathways in cancer cachexia and evaluate the therapeutic efficacy of targeting these pathways to diminish cancer cachexia.